1. Field of Invention
The present invention relates to a method of treating diseases caused by Herpes Simplex Virus (hereafter referred to as HSV) Types 1 and 2. More specifically, the invention relates to the parenteral, topical and/or oral administration of the tetraethylammonium ion (hereafter sometimes referred to as TEA) either before or after the HSV has infected the host.
2. Prior Art and General Background
There are two main strains of Herpes Simplex Virus (HSV), Types 1 and 2. Although they are capable of strong cross reaction in some assays, they can be differentiated by neutralization kinetics and, with greater accuracy, by restriction analysis of their purified deoxyribonucleic acid (DNA). Generally, infection by HSV Type 1 is associated with oral, facial and ocular lesions; infection by HSV Type 2 with genital and anal lesions.
Both HSV Types 1 and 2 show a predilection for ectodermal tissues such as in their production of lesions in skin, oral cavity, vagina, conjunctiva and the nervous system. HSV Type 2, which is usually transmitted venereally, is now epidemic in the U.S.A. Some twenty million persons are presently afflicted with this disease in this country. New cases and recurrences exceed 500,000 annually. HSV infections often cause blindness, neonatal deaths, encephalitis, etc. and additionally results in huge economic losses to the nation and the world.
(i) Pathogenesis of HSV Disease
An important characteristic of these viruses is their ability to persist in a latent, or quiescent, form in man and animals.
Initial or primary infections by HSV Types 1 and 2 are contracted through breaks in the mucus membrane where they replicate locally. From there they spread to the regional lymph nodes and, occasionally, they can invade the bloodstream, producing viremia.
When the primary infection subsides or recedes, the virus persists in a latent form in the sensory ganglia which innervate the site of primary infection. In ocular or oral infections, the viruses persist in the trigeminal ganglia. In genital infections, the viruses persist in the sacral ganglia.
Although the state of the viral genome during latency is not yet known, latency can be upset, resulting in viral multiplication. This produces the second form of the disease, which is the recurrent form. Recurrences usually occur at the primary sites. Such recurrent disease in humans can be induced by heat, cold, sunlight (ultraviolet light), hormonal and emotional disturbances, or by immunosuppressive agents.
The natural source and host for HSV Types 1 and 2 disease is man and the primary mode of transmission is by close personal contact.
(ii) Epidemiology of HSV Diseases
Epidemiological control of HSV is poor because the majority of the population, up to 90%, has been exposed to the viruses. In the healthy carrier the viruses can be isolated in the tears, saliva, vaginal and other secretions, even during the absence of overt disease.
Past treatments of the disease have been largely ineffective. To successfully stop the growth of a virus, an agent must selectively inhibit any of the viral specific functions such as (1) adsorption, (2) uncoating, (3) transcription, (4) protein synthesis, (5) nucleic acid replication, (6) maturation, and (7) release.
Among agents thus far used to treat HSV are: Idoxuridine (IDU), Cystosine Arabinoside (ARA-C), Adenine Arabinoside (ARA-A), Trifluorothymidine (TFT), and Acyclovir. Interferon has also been used for HSV treatment. All of these therapies interfere with viral and host cellular functions. Because of host cell toxicity these compounds have been largely ineffective for systemic use in humans.
Until this invention there has been no drug shown to be capable of selective inhibition of viral function. The inventor has demonstrated that TEA in the manner utilized does selectively inhibit viral function. The anti-viral properties of TEA toward HSV Types 1 and 2 is shown by the results in the detailed description of the invention given below. Similar properties are expected of the homologues of TEA.
It is therefore an object of the present invention to provide an effective method of treating HSV Types 1 and 2.
The present invention is directed to the use of TEA ion to treat HSV Types 1 and 2. The TEA ion has the following structure: ##STR1##
TEA chloride is listed in the American Druggist's Blue Book (1974) Am. ed. as being sold by: City Chemical Corp., 132 W. 22nd Street, New York, NY 10011.
Description of a process for manufacture of TEA is given in U.S. Pat. No. 2,653,156 Sept. 22, 1953 by Deutsch, et al. which also notes generally the disinfectant properties of quaternary ammonium compounds of which TEA chloride is one.
Similarly, U.S. Pat. No. 4,165,375 issued Aug. 21, 1979 to Berger et al. contemplates the general use of quaternary ammonium compounds in a low foaming medium for external use as a general disinfecting agent.
U.S. Pat. No. 2,689,814, issued Sept. 21, 1954 to Nicholls et al. similarly noted the germicidal effectiveness of TEA as well fungicidal and anesthetic properties of quaternary ammonium compounds. U.S. Pat. No. 2,886,487 issued on May 12, 1959 to Kupferberg et al. also describes the use of such quaternary ammonium compounds in topical application.
In the 1949 edition of the Physicians' Desk Reference, the product "Etamon Chloride," was reported to contain 0.1 g of tetraethylammonium chloride in each cc. and described, to-wit; "reversibly blocks transmission of the motor impulses of both the sympathetic and parasympathetic divisions of the autonomic nervous system. In conditions associated with vasospasm it causes vasodilation. Used in herpes zoster, postherpetic pain, causalgia, thromboangiitis obliterans (Buerger's disease), Raynaud's disease, thrombophlebitis, trenchfoot, and immersion foot." In the 1954 edition of Physicians' Desk Reference any claim with respect to herpes zoster was omitted. In the 1960 edition of the Physicians' Desk Reference the product was no longer listed, and subsequently the manufacture of the product in pharmaceutical purity was discontinued. It is further noted that this product contained as a preservative benzethonium chloride, which preservative, in accordance with U.S. Pat. No. 4,262,007 to Sherrill (issued Apr. 14, 1981), is effective in treating herpes zoster, etc.
In The Pharmacological Basis of Therapeutics (2nd Ed.) by Goodman and Gilman (1955; MacMillan) in a discussion of the therapeutic uses of TEA, TEA's role as a pain reliever was mentioned in relation to, inter alia, herpes zoster as follows: "In various types of causalgia and related painful posttraumatic states, herpes zoster, and chest pain caused by embolism, neoplasm, pleuritis, etc., TEA is of value in relieving pain, in a few instances permanently, and may be a useful diagnostic tool for selecting cases which might be relieved by sympathectomy".
Additional prior patents which may be of interest are listed below:
______________________________________ Patent No. Patentee(s) Issue Date ______________________________________ 2,295,504 Shelton Sept. 8, 1942 2,666,009 Stayner Jan. 12, 1954 ______________________________________